New piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives as selective 5-HT1A receptor agonists with highly potent anti-ischemic effects

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 12; pp. 2990 - 2993
• Main Authors: KAMEI, Katsuhide, MAEDA, Noriko, KATSURAGI-OGINO, Ryoko, KOYAMA, Makoto, NAKAJIMA, Mika, TATSUOKA, Toshio, OHNO, Tomochika, INOUE, Teruyoshi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 15.06.2005
• Subjects: Adrenergic alpha-1 Receptor Agonists; Animals; Arterial Occlusive Diseases - drug therapy; Arterial Occlusive Diseases - metabolism; Biological and medical sciences; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Cerebrovascular Circulation - drug effects; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - metabolism; Medical sciences; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - pharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Receptors, Dopamine D2 - agonists; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - chemistry; Serotonin Receptor Agonists - pharmacology; Serotoninergic system; Structure-Activity Relationship; Nervous system diseases; Agonist; Rat; Rodentia; Cardiovascular disease; Neuroprotective agent; Selectivity; In vitro; Pyridine derivatives; Vascular disease; In vivo; Vertebrata; Mammalia; 5-HT1A Serotonine receptor; Structure activity relation; Animal; Central nervous system disease; Piperidine derivatives; Affinity; Pyrimidine derivatives; Models; Antiïschemic; Cerebrovascular disease
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.04.059

A series of new piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives were synthesized. Among these compounds, 4-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine derivative 23 (SUN N5147) exhibited sub-nanomolar affinity for 5-HT1A receptor with 1000-fold selectivity over both dopamine D2 and alpha1-adrenergic receptors and remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.